This project is concerned with the phenomenon of immunologic reactivity to degradation products of total hip arthroplasty (THA) components leading to bone loss and implant failure. This proposal focuses on ionic and particulate biomaterial-induced cellular responses of lymphocytes and monocytes/macrophages in patients with THA. It continues to be observed clinically that some patients with total joint arthroplasties can tolerate particulate burden and metal-protein complex formation for long periods of time (>8 years) with relatively little peri-implant reactivity, whereas other patients with seemingly equivalent particulate and ionic burdens demonstrate pronounced reactivity within 2-7 years, resulting in peri-implant bone resorption. Cells of the immune system primarily mediate these events. Particles phagocytosed by macrophages and metal-protein complexes interacting with lymphocytes can lead to the production of factors which act in both an autocrine and paracrine fashion and contribute to either increased bone resorption or reduced bone formation. In our preliminary work, it has been shown that 1) markers of catabolic bone changes are elevated after THA; 2) lymphocytes from selected patients with THA are hyper-responsive to certain metal salts; and 3) monocytes from patients with THA are in a sensitized state and produce larger amounts of cytokines and eicosanoids in response to challenge with particulate debris than monocytes isolated from normal individuals. We hypothesize that serum markers of immune reactivity and collagen catabolism are elevated in THA patients prone to osteolysis and aseptic loosening and that ionic (metal-protein complexes) and particulate implant debris produce diverse levels of reactivity in different individuals, in part, through variable activation of cells of the immune system. We propose to test these hypotheses by correlating serum and urine markers of inflammation and Collagen catabolism with the development of osteolysis in a wellcharacterized cohort of THA patients with and without osteolysis at a single time point (Groups AI-A4), and then to use these identified markers to indicate the onset of osteolysis prior to the development of clinical symptoms and/or radiographic changes within the annually collected serum and urine of a prospectively followed cohort of patients (Groups 131-134). Additionally, variable immunologic responses induced by implant degradation products (i.e. lymphocyte response to metal ions and monocyte/macrophage response to particulate debris) will be correlated with the development of osteolysis